Curr Allergy Asthma Rep (2017) 17: 56

DOI 10.1007/s11882-017-0725-y

ANAPHYLAXIS AND DRUG ALLERGY (DA KHAN AND M CASTELLS, SECTION EDITORS)

Update on Quinolone Allergy

Inmaculada Doña 1 & Esther Moreno 2,3 & Natalia Pérez-Sánchez 1 &
Inmaculada Andreu 4 & Dolores Hernández Fernandez de Rojas 5 & María José Torres 1

Published online: 27 July 2017

# Springer Science+Business Media, LLC 2017

Abstract clinical pictures, the methods used for diagnosing and the
Purpose of Review Quinolones are a group of synthetic anti- management of allergic reactions to quinolones.
biotics widely use as first-line treatment for many infections. Recent Findings Allergic reactions to quinolones can be im-
There has been an increase in the incidence of hypersensitivity mediate or delayed, being anaphylaxis and maculopapular ex-
reactions to quinolones in recent years, likely due to increased anthema respectively the most frequent clinical entities. A pre-
prescription. The purpose of this review is to summarize the cise diagnosis is particularly difficult since clinical history is
often unreliable, skin tests can induce false-positive results, and
This article is part of the Topical Collection on Anaphylaxis and Drug commercial in vitro test are not well validated. Therefore, drug
Allergy provocation testing is considered the gold standard to establish
diagnosis, which is not a risk-free procedure. Cross-reactivity
* Inmaculada Doña between quinolones is difficult to predict due to the small num-
inmadd@hotmail.com
ber of patients included in the few published studies. Moreover,
Esther Moreno
hypersensitivity to quinolones has also been associated with
emrodilla@gmail.com beta-lactam and neuromuscular blocking agent allergies, al-
though further studies are needed to understand the underlying
Natalia Pérez-Sánchez
natbel.ps@gmail.com mechanisms. Avoidance of the culprit quinolone is indicated in
patients with a diagnosis of hypersensitivity to these drugs.
Inmaculada Andreu
iandreur@qim.upv.es
When quinolone treatment is the only therapeutic option avail-
able, desensitization is necessary.
Dolores Hernández Fernandez de Rojas Summary This review summarizes the complex diagnostic
hernandez_dol@gva.es
approach and management of allergic reactions to quinolones.
María José Torres
mjtorresj@ibima.eu
Keywords Anaphylaxis . Basophil activation test . Drug
1
provocation test . Maculopapular exanthema . Quinolone .
Allergy Unit, Pabellón 6, primera planta, IBIMA Regional
Skin test
University Hospital of Malaga-UMA (Pavillion C, Hospital Civil),
Plaza del Hospital Civil, 29009, Malaga, Spain
2
Allergy Service, University Hospital of Salamanca,
Salamanca, Spain Abbreviations
3
Institute for Biomedical Research of Salamanca (IBSAL),
AGEP Acute generalized exanthematous pustulosis
Salamanca, Spain BAT Basophil activation test
4
Unidad Mixta de Investigación IIS La Fe-UniversitatPolitècnica de
DR Delayed reactions
València, Hospital Universitari i Politècnic La Fe, Avenida de DPT Drug provocation test
Fernando Abril Martorell 106, 46026, Valencia, Spain ELISA Enzyme-linked immunosorbent assay
5
Department of Allergy, Hospital Universitari i Politècnic La Fe, FDE Fixed drug eruption
Valencia, Spain IR Immediate reactions
56 Page 2 of 10
IDT Intradermal test
MPE Maculopapular exanthema
NMBA Neuromuscular blocking agent
RAST Radioallergosorbent test
SPT Skin prick test
SJS Stevens-Johnson syndrome
TEN Toxic epidermal necrolysis
Introduction
Quinolones are a group of synthetic antibiotics with a wide
range of activities against both gram-negative and gram-
positive bacteria [1]. In recent years, there has been a large
increase in the use of quinolones as first-line treatment, espe-
cially in immunocompromised patients which are susceptible
for bacterial infections [2, 3]. The most widely used members
of this group of antibiotics are the fluoroquinolones, being
ciprofloxacin, the most frequently used worldwide [1].
Quinolones are generally well-tolerated antibiotics; howev-
er, adverse effects have been reported, including hypersensitiv-
ity reactions. In the last few decades, there has been an increase
in the incidence of hypersensitivity reactions to quinolones [4],
some of which have been severe, including anaphylactic reac-
tions, acute exanthematic reactions, and toxic epidermal
necrolysis (TEN) [5]. This increase in incidence of hypersensi-
tivity reactions to quinolone is likely due to an increased pre-
scription of these drugs as first-line treatment [2, 3].
Classification and Chemical Structure of Quinolones
The first quinolone antibiotic drugs were developed in the
1960s, namely nalixidic acid and cinoxacin. Their basic struc-
ture is formed by a bicyclic skeleton; the carboxylic acid and
ketone groups at the 3 and 4 positions, respectively, are essen-
tial for their pharmacological activity (Fig. 1a). In order to
improve their antibacterial spectra, modification by means of
introduction of a fluorine atom in the chemical structure
yielded the so-called fluoroquinolones. Thus, it has been
established that a cyclopropyl group at position 1, a
piperazinyl ring at C-7 and a halogen atom (generally fluo-
rine) at C-6, and to a lower extent at C-8 enhance the antibac-
terial activity of these antibiotics.
Quinolones can be classified by different criteria: chemical
structure, antibacterial spectra, and pharmacokinetic features. In
this review, they are classified according to generation, which
correlates with their antibacterial spectra [6] (Fig. 1b). The first
generation agents display narrower spectra than the later ones.
Curr Allergy Asthma Rep (2017) 17: 56
Epidemiology and Risk Factors for Quinolone
Allergy
Although hypersensitivity reactions to quinolones are consid-
ered unusual [7], their incidence has been rising, and they are
now the non-beta-lactam antibiotics most frequently involved in
drug hypersensitivity [4, 7, 8•] and the third leading cause of
confirmed hypersensitivity to drugs [4]. Among hospitalized
patients, quinolones are the second most frequent antibiotics
reported in allergy/intolerance alerts [9]. This is likely due to
their increased prescription and the introduction of moxifloxacin
[7], which has been shown to be the most frequent trigger of
quinolone reactions, followed by ciprofloxacin and levofloxacin
[10••]. Most hypersensitivity reactions to quinolones are imme-
diate reactions (IR), which are IgE-mediated. Importantly, reac-
tions are severe for 70% of cases [10••, 11•, 12••].
On the basis of spontaneous reports of anaphylaxis induced
by quinolones, in the last decades there has been an increase in
the total number of cases of anaphylaxis [11•], with an esti-
mated incidence of 1.8–2.3 per 10,000,000 days of treatment
[7] and representing 4.5% of drug-induced anaphylaxis [13].
Although all quinolones have been implicated in anaphylaxis,
moxifloxacin has been shown to be the most common culprit
[14], followed by levofloxacin and ciprofloxacin [11•, 12••,
15]. Moreover, reactions induced by moxifloxacin were more
severe, with 75% of reactions including anaphylaxis or ana-
phylactic shock [12••]. Though less common than IR, delayed
reactions (DR), which are T cell-dependent reactions, have
also been reported [16, 17, 18•, 19–22]. In this case, cipro-
floxacin is the most frequent culprit drug, followed by
levofloxacin and moxifloxacin [15, 23, 24].
Considering risk factors, it has been reported that 21% of
penicillin-allergic patients develop allergy to non-beta-lactam
antibiotics such as quinolones, compared to just 1% of those
who are not penicillin allergic [25]. In fact, a previous diag-
nosis of IR to beta-lactam antibiotics has been shown to be a
strong risk factor for developing quinolone allergy (OR
23.654; 95% CI 1.529–365.853; p = 0.024) [10••]. This is
especially relevant for immunocompromised patients, as the
prohibition of two groups of first-line antibiotics may worsen
the prognosis. It is unclear whether this is due to an inherent
predisposition to developing allergy or because patients diag-
nosed as allergic to beta-lactams are more likely be prescribed
quinolone [10••]. Moxifloxacin has been shown to increase
the odds of suffering an IR by fourfold compared to those of
other drugs (odd ratio [OR] 4.20; 95% confidence interval
[CI] 3.19–5.55) [14]. However, ciprofloxacin has been asso-
ciated with a higher risk of developing severe cutaneous DR
(OR 6.9; 95% CI 1.8–27) [26] compared with those of other
drugs; norfloxacin, ofloxacin, and ciprofloxacin have been
associated with a higher risk of acute generalized exanthema-
tous pustulosis (AGEP) (OR 33; 95% CI 8.5–127) [27] com-
pared to that of other quinolone.
Curr Allergy Asthma Rep (2017) 17: 56 Page 3 of 10 56

b
First generation

Second generation

Fig. 1 a General chemical structure of quinolones. b Classification of quinolones by antibacterial spectra

The Clinical Picture
Allergic reactions to quinolones can be classified as IR if they
appear within 1 h after drug intake, and DR if they appear
more than 1 h after drug intake. Most published studies
reporting IR after quinolone administration are case reports
or small series [5, 16, 17, 18•, 19–21, 27–35].
Clinical entities typical for IR are urticaria with or without
angioedema (31.6–85%), anaphylaxis (32.8–42.1%), and
shock (13–26.3%) [35, 36••]. Any quinolone may be
56 Page 4 of 10 Curr Allergy Asthma Rep (2017) 17: 56

Third generation

Fourth generation

Fig. 1 (continued)

involved, however, the most common triggers are ciprofloxa-
cin (23.2–43.7%), moxifloxacin (15.4–63.2%), and
levofloxacin (7.9–38.5%) [8•, 12••, 34, 35, 36••].
DR to quinolones is less common. Maculopapular ex-
anthems (EMP), normally not severe [34], and fixed drug
eruption (FDE) [22, 37, 38]are the most commonly re-
ported reactions [18•, 34, 35, 39]. Quinolones are one of
the most common drugs inducing photo allergy,
representing up to 38% of cases [40]. DR can also include
other less frequent entities, such as AGEP [41], Stevens-
Johnson syndrome (SJS), and TEN [19, 42], hematologic
disorders and organ-specific reactions [27]. The most
frequently involved quinolone in DR are ciprofloxacin,
followed by moxifloxacin, ofloxacin, and levofloxacin
[18•, 34, 35].
Diagnostic Procedures
Diagnosis can be performed based on clinical history
and in vivo and in vitro testing. However, these methods
have serious limitations and a precise diagnosis can be
difficult.
Curr Allergy Asthma Rep (2017) 17: 56 Page 5 of 10 56

Clinical History results because of irritant and histamine-releasing effects

The most reliable initial approach for evaluating allergic reactions
to quinolones is a detailed clinical history (Fig. 2). This must be
obtained carefully and should include the symptomatology and
chronology of the symptoms (including the latency period be-
tween the last dose and the onset of symptoms and time of
resolution). The time interval between both the first and last dose
and the occurrence of the reaction is useful for classifying reac-
tions as IR or DR. Other important details are as follows: age,
sex, personal history of atopy and documented hypersensitivity
to other drugs, family history of drug allergy, other medications
taken simultaneously, how long the patient was taking the culprit
drug before the reaction occurred, the last time the patient toler-
ated any type of quinolones, and whether the patient had previ-
ous episodes of reactions to the same drug or others belonging to
the same group. The ENDA/EAACI questionnaire can be very
useful to ensure these data are recorded in a uniform format [43].
However, the clinical history can be imprecise in many
cases, especially when the time elapsed between the reaction
and evaluation is prolonged. In this case, other diagnostic
methods are needed to achieve diagnosis: skin tests, in vitro
tests, and drug provocation testing (DPT).
Skin Tests
Skin tests may be used for the evaluation of suspected quino-
lone reaction (Fig. 2); although, its utility is controversial due
to both a low sensitivity and a high rate of false-positive
[27, 34, 36••, 44, 45].
For IR, the procedure generally begins with skin prick test-
ing (SPT). If this is negative, intradermal testing (IDT) is used.
SPT often gives false-negative results, while IDT can give
false-negative results at low concentrations and false-
positive results at high concentrations. Several authors have
investigated optimal concentrations for IDT by looking for
non-irritant concentrations; however, the studies give contra-
dictory results. Barbaud et al. suggest 0.2 mg/mL for IDT with
ciprofloxacin and 5 mg/mL for ofloxacin [46]. Broz et al.
recommended an IDT of 1:300 to 1:1000 for ciprofloxacin
[47]. In contrast, Empedrad et al. found a 100-fold dilution
as always irritant in the non-sensitized control group [44].
They observed considerable variability in the response to cip-
rofloxacin and were unable to identify a definitive nonirritant
concentration. Scherer et al. yielded 2 mg/mL × 10–3 as op-
timal threshold concentration for non-irritant IDT with cipro-
floxacin [27]. Seitz et al. also found positive reactions in con-
trols with concentrations ranging from 0.0002 to 0.2 mg/mL
[34]. In the case of levofloxacin, Empedrad et al. suggested an
IDT concentration of 25 mg/mL × 10–3 [44]. For
moxifloxacin, non-irritant concentrations for SPT vary be-
tween 1 and 20 mg/mL and for IDT between 0.004 and
0.05 mg/mL [5, 31, 34]. However, some studies did not in-
clude controls and the majority was restricted to small num-
bers of cases. In a recent study, Uyttebroek et al. found posi-
tive IDT results in 10/14 patients and in 12/16 controls tested
with a parenteral formulation of moxifloxacin hydrochloride.
Two patients tested positive at the 1:1000 dilution, two

Fig. 2 Algorithm for the Clinical history

diagnosis and management of
patients reporting hypersensitivity Immediate Non-immediate
reactions to quinolones. SPT skin (<24h) (>24h)
prick test, IDT intradermal test,
PT patch test In vitro test
Basophil activation test/Radioallergosorbent test/ Lymphocyte transformation assay
Enzyme-linked immunosorbent assay

Skin tests Skin tests

SPT+ SPT-/ID +/- PT-/IDT+/- PT+

STOP Mild reactions Severe reactions Mild reactions Severe reactions

(urticaria, angioedema) (anaphylaxis, shock) (urticaria, MPE, FDE) (AGEP, SJS, TEN, organ-
specific reactions)

DPTwith Desensitization* DPTwith

the culprit + When a given quinolone
+ the culprit STOP
quinolone is the only therapeutic quinolone
option available

* DPT with analternative quinolone can be carried out if necessary according to the scarce evidence published:
• If nalidixacid is the culprit: DPT with levofloxacin or moxifloxacin
• If second-generation is the culprit: DPT with another different second-generation,levofloxacin and moxifloxacin
• If levofloxacin is the culprit: DPT with ciprofloxacin and moxifloxacin
• If moxifloxacin is the culprit: DPT with ciprofloxacin and levofloxacin
56 Page 6 of 10
patients at the 1:100 dilution, and six patients at the 1:10
dilution. Of the 16 controls, two tested positive at the 1:100
dilutions and 12 individuals at the 1:10 dilution [42].
Sensitivity and specificity of IDT calculated in this population
were 57 and 12%, respectively. Positive and negative predic-
tive values were 36 and 25%, respectively.
The evaluation of DR is usually performed by delayed-
reading IDT and patch tests [48]. These can be useful for
diagnosing AGEP [41]. However, in most published cases
of quinolone-induced FDE, patch tests were negative [37,
38]. Only one case report involved a positive patch test on
areas of previous lesions [22]. In a retrospective study,
Brajon et al. found that commercially available preparations
of different quinolones diluted to 30% in water or petrolatum
were non-irritant [49]. To detect photoallergic reactions,
photopatch tests with UVA light can be used [50].
Moreover, scarification of the skin prior to photopatch testing
to enhance drug penetration has been suggested to increase
sensitivity [27]. Studies of the role of patch tests or IDT in DR
to quinolones have shown contradictory results. Sensitivity
ranges widely depending on the symptomatology of the reac-
tion, diagnostic test used (IDT or patch tests), drug concentra-
tion, drug vehicle used in patch tests (petrolatum, dimethyl
sulfoxide, etc.) and if the test is only performed on unaffected
skin (or previously affected skin in FDE). Regarding delayed-
reading IDT, 80% of quinolone allergic subjects have been
reported to give positive test results, although the possibility
of an irritant response cannot be ruled out [35]. It has been
shown to be positive in 60% of cases with delayed-urticaria or
MPE, and 66.6% of which were ultimately confirmed as al-
lergic [35]. Regarding patch tests, results vary depending on
the study; positivity of allergic subjects can range from 0 to
50% [34].
In Vitro Tests
There are currently no validated commercial in vitro tests for
the evaluation of quinolone allergy. Therefore, most tests are
produced in-house. The two main in vitro methods are as
follows: basophil activation test (BAT) and immunoassay (ra-
dioallergosorbent test (RAST) and enzyme-linked immuno-
sorbent assay (ELISA)).
Several studies looked at the detection of quinolone-
specific serum IgE using RAST, obtaining a high specificity,
although sensitivity was low, ranging from 30 to 55% [12••,
36••]. The variation in sensitivity can be attributed to the type
of allergic reaction that was studied as well as the quinolone
investigated. It should be taken into account that a loss of
sensitivity to drugs over time has been reported for IgE-
mediated hypersensitivity reactions to beta-lactams [51],
dypirone [52], and neuromuscular blocking agents [53].
Therefore, it is possible that patients may give negative results
Curr Allergy Asthma Rep (2017) 17: 56
for quinolones too, if they are evaluated after a longer time
period [36••].
BAT has also been employed for diagnostic purposes for
hypersensitivity reactions to quinolones. Very diverse results
have been reported regarding sensitivity and reliability [12••,
29, 54, 55]. One study exhibited a sensitivity of around 70%
and gave positive results for 69% of cases with severe reac-
tions [12••], whereas in another study, all patients studied
showed negative results [29]. These differences may be due
to differences in the culprit quinolone and the hypersensitivity
reaction involved.
It therefore appears that quinolone-specific IgE and
BAT are potentially useful for the diagnosis of immediate
drug hypersensitivity reactions to quinolones; however,
their predictive value is far from absolute [56]. They
may be of some use for deciding whether to carry out
quinolone DPT in allergic patients, and perhaps future
work may see improvements; however, it should be
pointed out that one recent study proposed that due to
potential unreliability, DPT is currently necessary to
identify the culprit quinolone [57].
Regarding BAT sensitivity, ciprofloxacin shows a higher
sensitivity than moxifloxacin, even in the cases where
moxifloxacin is the culprit drug [12••]. These findings are
due to moxifloxacin being more sensitive to ambient labora-
tory light than ciprofloxacin during the performance of BAT,
generating higher drug photodegradation, and therefore, lower
amounts of drug-protein conjugates [58]. It is known that
quinolones, in particular fluoroquinolones, can cause
photoallergy. This is due to their photohaptenic properties;
they can bind covalently to proteins upon UVA exposure,
leading to immunological reactions. It has been shown that
peripheral blood mononuclear cells photomodified with quin-
olones by means of UVA light were able to stimulate cell
proliferation [59, 60].
In the particular case of photoallergic reactions, cross-
reactivity among 6-fluoroquinolones has been demonstrated
using a murine model [61]. An enhanced expansion of
CD4+TCRVβ13+ Th1 cells was found after in vitro stimula-
tion of immune lymph node cells with fluoroquinolones-
photomodified cells, suggesting the presence of a common
epitope recognized by fluoroquinolone-specific T cells, prob-
ably the piperazinyl ring at position 7 present in several
fluoroquinolones such as enoxacin, norfloxacin, ciprofloxa-
cin, and lomefloxacin.
Regarding DR, studies using the in vitro lymphocyte trans-
formation assay have been reported, confirming T cell in-
volvement in MPE and AGEP pathogenesis [18•, 27,
59]_ENREF_27. This technique has a higher sensitivity than
patch testing, which may be in due to the complex inflamma-
tory response in the skin, a low quinolone penetration capa-
bility through the skin or sub-optimal quinolone concentra-
tions [18•, 62].
Curr Allergy Asthma Rep (2017) 17: 56
Drug Provocation Testing
DPT is considered the gold standard to establish or exclude the
diagnosis of hypersensitivity to quinolone when no other test
is available. It is also useful to choose an alternative quinolone
if diagnosis is confirmed [35, 63] and to evaluate cross-
reactivity in patients who are skin test or in vitro test positive
(Fig. 2) [10••].
DPT should only be considered after balancing the risks
and benefits for the individual patient [34], as it is not a risk-
free procedure. It must be performed by trained personnel in a
clinical setting, where rapid and adequate treatment can be
administered if a reaction occurs [63].
DPT is usually performed in a single-blind placebo-con-
trolled manner, although in some cases, a double-blind proce-
dure may be necessary [63]. Doses and the number of steps
used in DPT vary depending on the study, ranging from a
single dose [3] to escalating doses until the therapeutic dose
is achieved [6, 10••, 26].
The necessity of DPT for quinolone hypersensitivity evalua-
tion is clear given that only 7–32% of suspected IR and DR to
quinolone who underwent DPT could be confirmed as allergic
[34, 35], indicating that clinical history alone is often an unreli-
able indicator of true quinolone hypersensitivity and can lead to
over-diagnosis. Moreover, a loss of sensitivity to drugs over time
has been reported for IgE-mediated hypersensitivity reactions, as
has been shown in immediate reactions to beta-lactams [51],
dypirone [52], and neuromuscular blocking agents [53].
Therefore, the time interval between the suspected hypersensitiv-
ity reaction and the allergological study should be as short as
possible to avoid false-negative results.
Cross-Reactivity
Cross-Reactivity Between Quinolones
The presence of cross-reactivity between quinolones remains
a controversial issue. It has been suggested to be associated
with the common quinolone structure, a 4-oxo-1,4-
dihydroquinoleine ring core that may act as the antigenic de-
terminant [64], although the structure of groups bound to the
C1, C5, C7, and C8 positions may also play a role.
Different patterns of cross-reactivity have been established
for IRs and DRs to quinolones, although most published stud-
ies assessing cross-reactivity are case reports or small studies
with few subjects. In IR, a high degree of cross-reactivity has
been reported between the first- (nalidixic acid) and second-
generation (norfloxacin and ciprofloxacin) quinolone [28].
Cross-reactivity among quinolones from the second genera-
tion does not always occur [16, 33, 65] despite their similar
chemical structures. Differences in reactivity patterns may be
due to the production of different metabolites.
Page 7 of 10 56
Similarly, cross-reactivity between the newer quinolones
(moxifloxacin) and the second (ciprofloxacin) and third gen-
eration (levofloxacin) has been suggested to be lower [5, 7, 31,
32]. Regarding levofloxacin, a low degree of cross-reactivity
with ciprofloxacin has been found [8•].
In vitro studies of IR to quinolones also suggest a high level
of cross-reactivity. Using Sepharose-RAST, sIgE toward more
than one quinolone was detected in 63.6–80% of cases, al-
though only 16% of these patients reported a reaction to sev-
eral quinolones [12••, 36••]. Regarding BAT, positive results
from more than one quinolone have been found in 48.2% of
cases [12••, 58]. BAT cross-reactivity in hypersensitivity reac-
tions to moxifloxacin was observed to be higher than in hy-
persensitivity to ciprofloxacin since patients allergic to
moxifloxacin were positive to ciprofloxacin in most cases,
whereas patients were generally not positive to moxifloxcin
when ciprofloxacin was the culprit drug. This suggests that
IgE can recognize the chemical structure of ciprofloxacin de-
spite the reaction being induced by moxifloxacin [12••].
Therefore, in vitro cross-reactivity may over represent true
cross-reactivity based on DPT.
In DR, different grades of cross-reactivity between quino-
lones from different generation have been reported for the
different clinical entities [42, 66, 67]. An evaluation of the
recognition of ciprofloxacin-specific T cell clones from pa-
tients who have suffered MPE [18•] showed three main pat-
terns: clones that reacted only to ciprofloxacin; others that
reacted to two related quinolones, ciprofloxacin, and
norfloxacin; and clones that reacted to up to five quinolones
[19, 22, 65]. A study of photo-reactivity in a murine model of
photo-allergy showed cross-reactivity between six
fluoroquinolones for both in vivo and in vitro responses.
This suggests that photo-haptens also share a common epitope
that is recognized by T cells, particularly Th1 [60]. In vitro
cross-reactivity studies seem to indicate that T cells recognize
a common structure whereas IgE recognizes smaller compo-
nents such as side chains or smaller groups, although with
lower affinity [68].
Cross-Reactivity between Quinolones and Other Drugs
In addition to the cross-reactivity between different quinolones,
an important issue is the presence of concomitant allergies to
other non-chemically related drugs. It has been reported that in
the case of IgE-mediated reactions, patients previously diagnosed
as allergic to beta-lactams are more prone to develop allergy to
non-beta-lactam antibiotics (21%) than those who were not al-
lergic (1%) [69], being previously confirmed hypersensitivity to
beta-lactams, a risk factor for the development of hypersensitivity
to quinolones (OR: 23.654) [10••].
Moreover, IR to quinolones has also been associated with
neuromuscular blocking agent (NMBA) sensitization.
Quaternary ammonium sIgE has been detected in 53% of
56 Page 8 of 10
patients with IR to fluoroquinolones suggesting cross-
reactivity with neuromuscular blocking agents [70••]; howev-
er, the clinical relevance of this finding requires investigation
in vivo. As with NMBAs, quinolones can induce IR after a
single use [11•, 70••], suggesting that sensitization was in-
duced by another component that shares a common antigenic
determinant [11•].
Management
Avoidance of the culprit quinolone is indicated in patients
with a diagnosis of hypersensitivity to these drugs.
Tolerance to another quinolone should be assessed if neces-
sary, especially for patients with a previous history of hyper-
sensitivity to other antibiotics; for these patients, the therapeu-
tic possibilities would otherwise decrease dramatically (Fig.
2). It must be taken into account that cross-reactivity between
quinolones is still not fully known due to the small numbers of
patients included in the studies published so far [6, 10••, 11•,
25, 28, 29]. When a given quinolone is the only therapeutic
option available, desensitization may be required. Only three
cases of desensitization in patients with IR have been reported,
all induced by ciprofloxacin [71–73] and confirmed by DPT
or skin tests. Desentization in patients with DR has been re-
ported in a few cases [17, 74]. They were induced by cipro-
floxacin and confirmed by DPT. Although the induction is
normally temporary, one case has been described in which
long-term tolerance to ciprofloxacin was achieved after the
desensitization of a patient with a history of FDE-related to
this drug [17].
Conclusions
The number of documented cases of hypersensitivity to quin-
olones has increased in the last few decades, particularly for
IR and for reactions induced by moxifloxacin. Diagnosis is
complex, since clinical history is often unreliable, skin tests
can induce false-positive results and in vitro tests are not well
validated. Therefore, in many cases, the only way to diagnose
tolerance is with DPT, a procedure that can carry some risks.
Quinolones present a variable degree of cross-reactivity that is
unclear and difficult to predict. Importantly, hypersensitivity
to quinolones may be influenced by allergy to other drugs
such as beta-lactams and neuromuscular blocking agents, al-
though further studies are needed to understand the underlying
mechanisms and the clinical relevance.
Acknowledgements and Authors’ Contributions We thank James R.
Perkins for his help with the English language version of this manuscript.
MJT and ID compiled the entire manuscript; MJT contributed to the
introduction, management, and desensitization and conclusion sections;
Curr Allergy Asthma Rep (2017) 17: 56
IA contributed to the classification and chemical structure and in vitro
tests sections; EM contributed to the clinical reactions immediate and
delayed reactions, clinical history and skin tests sections; ID contributed
to the epidemiology and risk factors; drug provocation test and cross-
reactivity sections. All authors read and approved the final manuscript.
The present study has been supported by Institute of Health “Carlos
III” of the Ministry of Economy and Competitiveness (grants cofunded
by European Regional Development Fund (ERDF): RETIC ARADYAL
RD16/0006/0001. I Doña holds a Juan Rodes research contract
(JR15/00036) from the Carlos III National Health Institute, Spanish
Ministry of Economy and Competitiveness (grants cofounded by
European Social Fund, ESF).
Compliance with Ethical Standards
Conflict of Interest None of the authors have any conflict of interest,
nor have they received any money for this study. Research is part of their
daily activities. All authors had full access to all data and take responsi-
bility for the integrity and accuracy of the data analysis.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
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